The epidemic surge in the prevalence of obesity is one of the most serious public health problems confronting the western societies. For the first time in recent US history, the expected life span has declined due to an increase in the incidence and complications of obesity. Sixty-five percent (65%) of the adult population in the United States is overweight and over 30% is obese1. There has also been an increase in the obese pediatric population with one of three Americans born in the year 2000 are expected to suffer from the complications of obesity in their later lifetime2,3. Although causally linked to debilitating conditions such as insulin resistance, type 2 diabetes, atherosclerosis and cardiovascular disease, there remains limited effective therapeutic treatment for obesity4.
Leptin is an adipocyte-derived hormone that suppresses appetite mainly through its action on a subset of hypothalamic neurons5,6. It also allows the body to expend energy necessary for growth, reproduction and immunity7,8. Genetic leptin deficiency in mice and humans leads to a severe form of monogenic obesity due to unregulated appetite and reduced energy expenditure9-11. The discovery of leptin more than a decade ago created hope that it might be used therapeutically in the treatment of obesity; however, except for rare leptin-deficient individuals, both diet-induced rodent models of obesity and obese humans are minimally responsive to leptin due to development of leptin resistance in the brain and defects in transportation of leptin across the blood brain barrier12-16. The molecular mechanisms of leptin resistance are poorly understood. Suppressor of cytokine signaling 3 (SOCS3)14,17,18 and tyrosine phosphatase 1 B (PTB1B) have been shown to play important roles in the blockade of leptin signaling19. In addition, recent evidence has demonstrated that increased serine phosphorylation of Janus kinase 2 (Jak2) contributes to the blockade of leptin action20.
The endoplasmic reticulum (ER) is a sophisticated luminal network in which protein synthesis, maturation, folding and transport take place21,22. Perturbation of these processes in several different pathological states creates a condition defined as ER stress and leads to activation of a complex signaling network termed the unfolded protein response (UPR)23. Previous studies have demonstrated that ER stress and activation of UPR signaling pathways play a dominant role in the development of obesity-induced insulin resistance and type 2 diabetes24. Furthermore, reversal of ER stress with chemical chaperones—agents that have the ability to increase ER folding machinery—increases insulin sensitivity and reverses type 2 diabetes in obese mice25. The mechanisms underlying ER stress and activation of UPR signaling in obesity are not completely understood. Current evidence indicates that increased levels of circulating cytokines, free fatty acids (FFA), exposure to excess nutrition and subsequent activation of the mammalian target of rapamycin (mTOR) pathway23,25,26 contribute to the development of ER stress and activation of UPR signaling pathways.
Mice engineered to have reduced ER folding capacity24 or increased levels of ER stress27 develop a higher degree of obesity when challenged with a high fat diet. Because leptin receptor expressing neurons of the hypothalamus are exposed to ER-stress associated factors such as increased cytokines, FFAs and other nutrients28, we have sought to determine whether ER system is perturbed within the hypothalamus and may contribute to the phenomenon of leptin resistance and, in turn, to obesity itself.
The present invention is directed to overcoming these deficiencies in the art.